(a) Field of the Invention
The invention relates to G-protein-coupled receptor antagonists which bind to the intracellular molecular interface between the receptor for PGF.sub.2.alpha. (FP receptor) and the G-protein.
(b) Description of Prior Art
Prostaglandins are derived from the oxygenation of arachidonic acid by prostaglandin synthases. Prostaglandins mediate a wide variety of physiological actions, such as vasomotricity, sleep/wake cycle, intestinal secretion, lipolysis, glomerular filtration, mast cell degranulation, neurotransmission, platelet aggregation, leuteolysis, myometrial contraction and labor, inflammation and arthritis, patent ductus arteriosus, cell growth and differentiation. Prostanoids mediate their actions through binding to distinct receptors which belong to the super family of rhodopsin-like seven transmembrane helical receptors. These receptors are coupled to heterotrimeric G-proteins consisting of .alpha., .beta. and .gamma. subunits which, upon activation, elicit alterations in cell calcium, initiate phosphoinositide hydrolysis or promotion or repression of cyclic adenosine monophosphate synthesis (Strader, C. D., et al., Ann. Rev. Biochem. 63: 101-132, 1994).
Of the five pharmacologically distinct prostanoid receptors for E.sub.2, I.sub.2, D.sub.2, TxA.sub.2 and F.sub.2.alpha. and their many isoforms, the receptor for PGF.sub.2.alpha., also called FP receptor, shows limited tissue distribution, predominantly expressed in corpora leutea, uterine myometrium, trabecular meshwork of the eye, and to a lesser extent in vascular smooth muscle. Initiation of labor is marked by tremendous rise in PGF.sub.2.alpha. levels and increased uterine contractility. The wide spread use of PGF.sub.2.alpha. analogues to induce labor in veterinary industry points to the primary role of PGF.sub.2.alpha. and its receptor in parturition. This is underscored by the fact that mice lacking the FP receptor fail to undergo labor (Sugimoto, Y., et al., Science, 277: 81-83, 1997).
In face of escalating costs incurred as a result of premature births and associated complications to the neonate, such as intraventricular hemorrhage, bronchopulmonary displasia and periventricular leukomalacia leading to cerebral palsy, prolongation of gestation by arresting premature labor is an effective preventive therapy. The relative success of nonsteroidal anti-inflammatory drugs as a short term therapy toward prevention of premature labor is based on their inhibitory actions upon the synthesis of prostaglandins, particularly PGE.sub.2 and PGF.sub.2.alpha.. However, inhibition of the former is associated with serious complications to the fetus such as the closure of ductus arteriosus, renal failure and pulmonary hypertension. At another level, PGF.sub.2.alpha. has been attributed a major role in dysmenorrhea, a condition which afflicts 5%-7% of premenopausal women. A pre-menstrual increase in PGF.sub.2.alpha. levels resulting in myometrial spasms underlies the pathogenesis of this disorder. Lack of effective antagonists of FP receptor for extended therapy hampered the advances in preventing premature labor and associated sequelae.
Human FP receptor is a 45 kDa integral membrane glycoprotein, consisting of 359 amino acids and shares only 47% sequence identity with EP1 receptor, and to a lesser extent with other prostanoid receptors (Abramovitz, M., et al., J. Biol. Chem., 269: 2632-2636, 1994). Binding of PGF.sub.2.alpha. to FP receptor is followed by the activation of G.sub..alpha.q.beta..gamma. complex, increased GTP binding by the G.sub..alpha.q subunit, stimulation of phospholipase .beta. activity, release of inositol phosphates, increased intracellular calcium and subsequent signal transduction phenomena ultimately leading to smooth muscle contraction. The FP receptor is the only efficacious target for development of therapeutic drugs since a few G.sub..alpha. -proteins catalyze the actions of hundreds of G-protein coupled receptors, thus targets downstream from the receptor are essentially of little use.
Antagonists of FP receptors directed to the ligand binding site could be of limited use since ligand based inhibitors show cross reactivity with other prostanoid receptors; their efficacy will be compromised in face of tremendous increase in PGF.sub.2.alpha. concentrations in myometrium at the onset of labor; and the basal activity of the receptors in the absence of ligand limits the use of ligand-based inhibitors.
It would be highly desirable to be provided with antagonists of FP receptors which do not cross-react with other prostanoid receptors and which are effective even in the absence of a ligand.